Investigator: Avelina Espinosa, Roger Williams University

Scientific Theme: Molecular Toxicology

Abstract: Anaerobic pathogens have acquired traits to survive and thrive in host guts. Understanding their adaptations to the luminal environment will provide the critical knowledge necessary to develop new drugs and better treatments of infectious diseases. This research proposes combining structural/biochemical analyses of anaerobic enzymes and ecological adaptations of these enzymes to develop improved strategies to manage amebiasis. Entamoeba histolytica, the etiological agent of amebiasis, causes infections of 50 million people every year and 100 thousand fatalities worldwide. Despite the epidemiological importance of E. histolytica, there are currently no ideal methods to prevent infection in areas without appropriate sanitation. The development of a vaccine for amebiasis, although promising, has not been successful, thus metronidazole is the present drug of choice to treat amebiasis. Luminal amebicides (e.g. diloxanide furoate) are effective on intestinal lumen trophozoites but unable to reach tissue ameba; tissue amebicides (e.g. metronidazole, dehydroemetine, chloroquine, nitazoxanide) are effective on treating invasive amebiasis but incapable of controlling luminal trophozoites. Additionally, toxic side effects (e.g. neurological, reproductive and potential carcinogenic concerns) have been reported for metronidazole and its derivatives, the strongest rationale for the search/design of novel antiamebic compounds is a drug that manages both invasive and luminal amebiasis. A comprehensive analysis of essential metabolic pathways and the ecological interactions of virulent and opportunistic parasites will generate more effective anti-infective agents against a broad range of anaerobic pathogens and highlight the importance of an evolutionary perspective in training students interested in pursuing health related professions. The aims are: 1) characterize the genetic, biochemical and structural properties of alcohol/aldehyde dehydrogenases (ADHE) in Entamoeba spp; 1a). Improve first generation synthetic pyrazolines as inhibitors of trophozoite growth; 2) refining amebiasis management via understanding biochemical signaling, aggregation and virulent behavior in E. histolytica.

Human Health Relevance: EhADH2 is the ideal target for the development of a novel classes of inhibitors to treat amebiasis, the gastrointestinal infection caused by E. histolytic that is estimated to cause 100,000 deaths per year. This study will provide hands-on experience to help students develop an understanding of the scientific method, the critical thinking and technical skills needed to pursue a career in science or in health related areas.